text: The structural similarities between the inhibitors are readily apparent. The appendages of the central core are typically symmetrical and have an imidazole-proline structure. The natural L-configuration of the proline derivatives was found to be critical for inhibition since the unnatural D-configuration had drastically weaker activity. The potency of the inhibitors was correspondingly sensitive to changes in the amine capping element. These observations suggest that the amine region of the molecules plays an important role in the inhibitory activity.
  Favorable characteristics in an NS5A inhibitor include high potency and long plasma half-life in order to achieve a once-daily-dosage. Slightly asymmetrical appendages, as seen in ledipasvir, were found to have distinctive benefits for the optimization of inhibitor potency and pharmacokinetics. The structure of the central core changes the spacing and the projection of the appendages as well as the position of the lipophilicity in the central core, which affects inhibitory activity notably. Structures with fused central rings consistently show greater inhibitory activity, whereas less lipophilic central cores provide weaker activity. Symmetrical bis-imidazol structures, such as daclatasvir, experience a loss in potency when fluorene is substituted for the biaryl group. This substitution also gives rise to some serious stability problems. However, a smaller lipophilic connector such as difluoromethylene generates the most potent inhibitor in an asymmetrical structure. Additionally, it provides improved bioavailability and more favorable plasma half-life. There is also a remarkable increase in potency when phenyl is replaced with naphthyl as a central core. This increase is significantly higher in an asymmetrical structure than it is in a symmetrical structure. In asymmetrical structures, a difference in potency between the phenyl-alkyne inhibitors demonstrates the importance of the position of the lipophilicity. A more centrally located alkyne, which is a less lipophilic connector than phenyl, improves potency.